1. Field of Invention
This invention relates to the use of the C-076 family of compounds, i.e. avermectins, for the prevention, treatment and control of various diseases in humans caused by dysregulation and/or dysfunction of various portions of the human nervous system. More particularly, this invention relates to the administration of the avermectin class of compounds (1) to prevent, treat, and control such diseases in humans as seizures, dystonic movements, tremors, degenerative conditions of the brain, spinal cord, and peripheral nerves, spasticity of both brain and spinal cord origin, and various types of psychoses and personality disorders, (2) to increase tonic activity of the parasympathetic nervous system, as in bladder and bowel control, (3) to decrease activity of the sympathetic nervous system at cutaneous and cardiovascular levels, (4) to ameliorate depression, (5) to regularize the sleep-wake cycle, (6) to decrease addictive and abusive behavior, (7) to increase attention span and improve behavior of mentally-deficient children and adults, (8) to treat autoimmune disorders, (9) to treat malignant states, and (10) to prevent or ameliorate anoxic or ischemic damage to the nervous system, as well as specific pharmaceutical formulations and treatment regimens for such prevention, treatment and control. The preferred compound which is used to illustrate this invention is ivermectin. Ivermectin is a semi-synthetic derivative of avermectin and is generally produced as a mixture of at least 80% 22,23-dihydroavermectin B.sub.1a and less than 20% 22,23-dihydroavermectin B.sub.1b. The following structural formula represents the avermectin series of compounds, which compounds can be chemically converted to useful derivatives as discussed below. ##STR1## wherein R is the 4'-(alpha-L-oleandrosyl)-alpha-L-oleandrose group of the structure: ##STR2## and wherein the broken line indicates a single or double bond; R.sub.1 is hydroxy and is present only when said broken line indicates a double bond; R.sub.2 is isopropyl or sec-butyl; and R.sub.3 is methoxy or hydroxy.
2. Prior Art
The avermectin family, of which ivermectin, a chemically produced analog, is a member, is a series of compounds isolated from the fermentation broth of a C-076 producing strain of Streptomyces avermitillis and also chemically produced derivatives thereof. At least eight distinct but closely related compounds are produced by S. avermitillis, A.sub.1a, A.sub.1b, A.sub.2a, A.sub.2b, B.sub.1a, B.sub.1b, B.sub.2a, and B.sub.2b. Their production is described in U.S. Pat. No. 4,310,519. The preparation of ivermectin is disclosed in U.S. Pat. No. 4,199,569. The disclosures of each of the foregoing patents are incorporated herein by reference. The avermectin family of compounds is a series of very potent antiparasitic agents known to be useful against a broad spectrum of endoparasites and ectoparasites in mammals and also to have agricultural uses against various nematode and insect parasites found in and on crops and in soil.
Some of the avermectins contain a 22,23-double bond. This may be selectively reduced to prepare the ivermectin compounds. In addition, the avermectins possess a disaccharide moiety at the 13-position consisting of the alpha-L-oleandrosyl-alpha-L-oleandrosyl group. One or both of these saccharide groups may be removed as described in U.S. Pat. No. 4,206,205. The thus produced aglycone derivatives have a hydroxy group at the 13-position. This group may be removed to form the 13-deoxy compound as described in U.S. Pat. Nos. 4,171,314 and 4,173,571; the latter patent also describes the 13-halo derivatives. The avermectin compounds and derivatives have several hydroxy groups which may be acylated as described in U.S. Pat. No. 4,201,861. Other derivatives of avermectin and ivermectin are disclosed in U.S. Pat. Nos. 4,333,925 and 4,963,667. All the aforementioned patents are incorporated herein by reference. The compounds disclosed in the patents mentioned above share the property of antiparasitic activity with ivermectin.
Since all the compounds mentioned and referred to above share the spectrum of anti-parasitic biological activity of ivermectin, varying only in degree, it is expected they will share the activity spectrum needed to make them suitable for use in this invention. In order to establish their potency and selectivity as compared to invermectin, other members of the avermectin class could be screened utilizing in vitro and in vivo models already known from the literature. Compounds which look promising for preventing, treating or controlling a particular indication in the in vitro screens are tested further in animal models. Those with the potency desired in the animal models are then further selected for testing in human pharmacodynamic models and clinical trials.
In vitro screens which are suitable include (1) the binding of the test compounds as radio labeled derivatives thereof to preparations of gamma-aminobutyric acid (GABA) receptors, sub-types A and B, (2) the displacement of the binding of other known GABA A and B receptor agonists by the avermectin compounds, (3) examination of the ability of either the avermectin compounds, or of other GABA agonists plus the avermectin compounds, to bind in the presence of GABA, and (4) effects of the avermectin compounds on the release and uptake of GABA by brain or nerve preparations. The tests described herein are disclosed in the following publications: Sigel, et al. Mol. Pharmacol., 32, 749-52 (1987); Soderlund, et al., Biochem. Biophys. Res. Comm. 146, 692-698 (1987); Kirkness, et al., Eur. J. Pharmacol., 150, 385-388 (1988); Robertson, Br. J. Pharmacol., 98, 167-176 (1989); Chu, et al., Neurol., 37, 1454-1459 (1987); Bhisitkul, et al., Exp. Brain Res., 66, 659-663 (1987); Kerr, et al., Brain Res., 405, 150-154 (1987); Price, et al., Nature, 307, 71-74 (1984); Bowery, et al., Neuropharmacol., 23, 219-231 (1984); Olsen, et al., FASEB J., 4, 1469-1480 (1990); and Erickson, Sci. Amer., 264(5), 124 (1991). All four types of assays can be performed using GABA preparations derived from different regions of the brain, spinal cord, peripheral nerves, and various body organs.
In vivo screens suitable for testing include using animal models for seizures and for spasticity. Suitable seizure models are disclosed in Porter, et al., Cleveland Clin. Quart., 51, 293-305 (summer 1984); McNamara, et al., Neuropharmacol., 27, 563-568 (1988); and McNamara, Epilepsia, 30 suppl, 513-518 (1989). Suitable spasticity models are disclosed in Coward, Triangle, 20, 151-158 (1981); Davies, Br. J. Pharmacol., 76, 473-481 (1982); Davies, et al., Br. J. Pharmacol., 78, 137-142, (1983), and Sayers, et al., Arzneimittel-Forschung, 30, 793-803 (1980).
Comparative human pharmacodynamic studies are then conducted using the compounds with the particular biological profile predicted from the in vitro and animal screens. The human tests which are suitable are disclosed in Hagbarth, J. Neurol. Neurosurg. Psychia., 23, 222-227 (1960); Hagbarth, et al., J. Neurol. Neurosurg. Psychia., 31, 207-213 (1968); Hassan, et al., J. Neurol. Neurosurg. Psychia., 43, 1132-1136 (1980); Knutsson, et al., Scand. J. Rehabil. Med., 12, 93-106 (1980); Knutsson, Triangle, 21, 13-20 (1982); Knutsson, et al., J. Neurol. Sci., 53 187-204 (1982); and Kugelbert, Electroenceph. Clin Neurophysiol., Suppl. 22, 103-111 (1962).
The only use for human patients described in the literature for the avermectins, and invermectin in particular, is for treating nematode parasites, particularly onchocerciasis (river blindness) utilizing dosages of up to 150 micrograms per kilogram of body weight. No side effects of significance were reported and no teratogenic activity was found, Pacque, et al., Lancet, 335, 1377-1380 (1990) and Pacque, et al., Lancet, 336, 1486-1489 (1990).
Many members of the avermectin class, in particular invermectin, are potent and highly selective parasiticides which are lethal for invertebrates from a variety of phyla, ranging from insects to nematode worms. Much work has been done to determine the mechanism of action and the safety for use in mammals. Many investigators conclude that ivermectin and avermectin B achieve their results in invertebrates by indirectly potentiating or mimicking the action of the neurotransmitter GABA. See Campbell, et al., Science, 221, 823-828, (1983); Campbell, et al., J. Vet. Pharmacol. Therap., 7, 1-16, (1984); Terada, et al., Exp. Parasitol., 57, 149-157, (1984); Bennett, JAVMA, 189, 100-104, (1986); Chalmers, et al., Eur. J. Pharmacol. 129, 371-374, (1986). Some investigators find other explanations and cast doubt on the accuracy of the GABA agonist theory. See Martin, et al., Br. J. Pharmacol. 98, 747-756, (1989). The parasites are believed to be killed as a consequence of centrally- or peripherally-mediated muscular paralysis. In the families of invertebrates affected, excessive GABA-ergic activity inhibits the process of neuromuscular transmission, see Bennett, supra.
Studies and experiments, attempting to determine if ivermectin exhibits GABA agonistic properties, have shown that ivermectin exhibits such properties in mammalian nervous tissues in vitro, at concentrations ranging from 10.sup.-7 M to 10.sup.-5 M, with levels of 10.sup.-6 M or higher generally being required to produce a 50% change in the parameters studied, Sigel, et al., (1987) supra; Soderlund, et al., (1987) supra; Kirkness, et al., (1988) supra; and Robertson, (1989) supra.
It was found by investigators that intravenous administration of 0.3 mg/kg in rats resulted in very small amounts of ivermectin entering the central nervous system. See Campbell, et al., (1983) supra; Campbell et al., (1984) supra, and Bennett, (1986) supra. Utilizing high doses in dogs and swine resulted in signs suggestive of activity at the level of the central nervous system. See Campbell et al., (1984) supra. However, in the investigations in vitro, the activity of ivermectin does not conclusively demonstrate that it acts as a GABA agonist. The results indicate it has a relatively slow onset of action, loses its activity within minutes of administration, and at times acts as a blocker rather than an activator of GABA-sensitive chloride channels, Sigel, et al., (1987) supra; and Robertson, (1989) supra; In mouse brain preparations, ivermectin may actually inhibit the channel-opening actions of GABA as noted by Soderlund, et al., (1987) supra. In guinea pig brain preparations, investigators found that many actions of ivermectin resemble those of the GABA antagonist picotoxin, Kirkness, et al., Turner (1988) supra.
In investigations to determine the effects of doses large enough to affect the central nervous system of mammals, the clinical signs produced indicated that the central nervous system was profoundly depressed, as evidenced by listlessness and ataxia, followed by loss of upright posture and death, Campbell et al., (1984) supra and Soderlund et al., (1987) supra, citing the unpublished paper of Bloomquist, et al.
There is nothing in the aforesaid publications which shows, speculates or predicts the effects of avermectins in general or ivermectin specifically on humans, i.e. on cardiovascular, gastrointestinal, parasympathetic or sympathetic systems, immune systems, on disease states or dysregulations of the nervous system, or on personality, mood, behavior, memory, attention span or cognitive status. Other GABA agonists known to be active in humans, such as the benzodiazepine tranquilizers, baclofen muscle relaxants and anti-convulsants such as valproic acid and gabapentin, are active to some extent in treating anxiety, as minor anesthesia agents, in treating spasticity, and for seizure control. They also have strong potential to cause cognitive changes, lethargy, somnolence, depression, psychotic behavior, respiratory depression, coma and death, particularly when taken in overdoses or for long periods of time. There is therefore a need for an active agent with GABA agonist properties that possesses all the beneficial effects of the putative GABA agonists, without the potential for toxicity of the other known members of this pharmacological class.